The use of natural products as traditional medicines, remedies, potions and
oils have been described since ancient times for the treatment of many diseases. Plant
derived natural products, in particular, represent a successful source for potential drug
leads. For instance, morphine, a mu opioid peptide receptor (MOPr) agonist, clinically
used as analgesic, is an alkaloid isolated from opium poppy of Papaver somniferum.
After its isolation, ongoing efforts in medicinal chemistry opened a wide program of
research aimed to discover analogues that maintain the analgesic profile of morphine
but reduced side effects. Analogously, mitragynine, an alkaloid isolated from the Thai
medicinal plant Mitragyna speciosa, showed morphine-like properties in pain animal
models although its chemical structure is different from that of morphine. Mitragynine
has analgesic, muscle relaxant, anti-inflammatory, anorexic effects and, similarly to
morphine, leads to tolerance and aversive withdrawal effects if chronically
administered. Mitragynine actions involve MOPr, neuronal Ca2+ channels and
monoaminergic system. Salvinorin A, extracted from Salvia divinorum, was used by
Indian tribes of southern California as an aid in childbirth. It is a kappa opioid peptide
receptor (KOPr) agonist with anti-addictive properties identified as a potential
treatment for drug abuse. In this chapter Salvinorin A and Mitragynine
pharmacological and chemical features, that made them suitable scaffolds for medicinal
chemistry approaches, are described. Our efforts are focused on the description of SAR
(structure-activity relationship) of salvinorin A and mitragynine derivatives developed
to obtain a reduced burden of undesirable effects.
Keywords: Antinociception, Biased opioid ligands, Delta opioid receptor, Kappa
opioid receptor, Mitragynine, Mu opioid receptor, Opioid, Pain, Salvinorin A,
Structure-activity relationship.
